PROJECT SUMMARY/ABSTRACT In one-third of strokes, a definite cause cannot be established. This proposal seeks to determine if some of these strokes in fact resulted from unrecognized atherosclerotic plaque in the arteries leading to the brain. Currently, only atherosclerotic plaques that cause significant stenosis (narrowing) of an artery are treated as the underlying cause of a stroke. However, pilot data suggest that nonstenosing plaques?plaques that have not caused arterial narrowing?can rupture and produce clots that travel downstream to block blood flow to the brain. Magnetic resonance imaging (MRI) can reliably determine which plaques have the highest risk of rupture. Such markers can identify high-risk nonstenosing plaques in the internal carotid arteries, which supply the majority of the brain's blood flow. In a patient with a stroke of unknown cause, pilot studies have found that the stroke is more likely to have occurred on the side of a carotid artery with high-risk nonstenosing plaque than on the opposite side where no high-risk plaque is present. The tendency of strokes to occur downstream of a high-risk nonstenosing plaque supports this application's hypothesis: that atherosclerotic plaque in the cerebral circulation is associated with stroke even in the absence of significant arterial narrowing. Such nonstenosing plaques may explain a substantial proportion of strokes whose cause currently seems unknown. Better recognition of these plaques may lead to better stroke prevention. Prior clinical trials found that carotid endarterectomy/stenting was not effective for preventing stroke recurrence in patients with nonstenosing plaque, and such plaques are now ignored in clinical practice. However, no trial has tested carotid endarterectomy/stenting in only those stroke patients whose nonstenosing plaque entails a stroke recurrence risk high enough that the benefits of the procedure outweigh its risks. If successful, the research proposed in this application would identify a novel stroke risk factor and establish the scientific premise for a potentially transformative therapeutic strategy. This application is for a prospective observational study of 200 patients with stroke of unknown cause. A detailed MRI protocol will be used to detect intraplaque hemorrhage, a marker of high-risk nonstenosing plaque. In 150 of the subjects, a PET/MRI study will also be performed for additional insight into high-risk features such as plaque inflammation. Aim 1 will test the hypothesis that brain infarcts will be more common on the side of a high-risk nonstenosing plaque than the opposite side. Aim 2 will test the hypothesis that in-depth stroke evaluation will less often uncover an alternative explanation in subjects with high-risk nonstenosing plaque than in those without such plaques. Aim 3 will test the hypothesis that recurrent infarction will occur more often on the same side as high-risk nonstenosing plaque than on the opposite side. Validation of these hypotheses would set the stage for a multicenter, randomized trial of carotid endarterectomy/stenting in patients with cryptogenic stroke and ipsilateral high-risk nonstenosing plaque.